| 1. |
- Brignole, Michele, et al.
(author)
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Clinical controversy : methodology and indications of cardioneuroablation for reflex syncope
- 2023
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In: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. - 1532-2092. ; 25:5, s. 1-10
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Journal article (peer-reviewed)abstract
- In 2005, Pachon et al.1 proposed cardiac vagal denervation to treat neurally mediated syncope. Since then, a metanalysis of observational studies2 and a recent randomized controlled trial (RCT)3 have provided some evidence that cardioneuroablation (CNA) is able to prevent syncope recurrence at least during the first 2 years following the procedure in patients affected by reflex syncope. In brief, the recent metanalysis2 of 14 studies including a total of 465 patients reported an average freedom of syncopal recurrence in 92% of patients (95% confidence interval 88–95%) during follow-up. The only available open RCT3 reported 8% recurrence of syncope in the 24 patients randomized to CNA and 54% recurrence rate in 24 untreated controls (P = 0.0004) during 2-year follow-up. In all studies, after the ablation procedure, the patients demonstrated heart rate increase together with reduction of heart rate variability (indicating impaired parasympathetic stimulation of the heart) persisting at least for 2 years. This provides proof-of-concept for the modification of the vagal ganglia activity in the heart.Given these facts, it is likely that CNA will become increasingly popular among physicians caring for syncope patients in the years to come. Nevertheless, many issues concerning clinical indications, methodology, and long-term results remain unresolved. These issues constitute the background of this manuscript in which leaders in CNA and experts in syncope debated critical issues and aimed to find agreement and, if not possible, to highlight the controversies that could be addressed in future studies. The authors were initially requested to give their evidence-based opinion on several predefined motions. These were merged into a manuscript draft, which was subsequently critically revised by means of two rounds of comments.
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| 2. |
- Fedorowski, Artur, et al.
(author)
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Orthostatic Hypotension : Management of a Complex, But Common, Medical Problem
- 2022
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In: Circulation: Arrhythmia and Electrophysiology. - 1941-3084. ; 15:3
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Journal article (peer-reviewed)abstract
- Orthostatic hypotension (OH), a common, often overlooked, disorder with many causes, is associated with debilitating symptoms, falls, syncope, cognitive impairment, and risk of death. Chronic OH, a cardinal sign of autonomic dysfunction, increases with advancing age and is commonly associated with neurodegenerative and autoimmune diseases, diabetes, hypertension, heart failure, and kidney failure. Management typically involves a multidisciplinary, patient-centered, approach to arrive at an appropriate underlying diagnosis that is causing OH, treating accompanying conditions, and providing individually tailored pharmacological and nonpharmacological treatment. We (1) propose a novel streamlined pathophysiological classification of OH; (2) review the relationship between the cardiovascular disease continuum and OH; (3) discuss OH-mediated end-organ damage; (4) provide diagnostic and therapeutic algorithms to guide clinical decision making and patient care; (5) identify current gaps in knowledge and try to define future research directions. Using a case-based learning approach, specific clinical scenarios are presented highlighting various presentations of OH to provide a practical guide to evaluate and manage patients who have OH.
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| 3. |
- Fedorowski, Artur, et al.
(author)
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Underlying hemodynamic differences are associated with responses to tilt testing
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11, s. 1-6
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Journal article (peer-reviewed)abstract
- Aim of this study was to explore whether differences in resting hemodynamic parameters may be associated with tilt test results in unexplained syncope. We analyzed age, gender, systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR) by merging three large databases of patients considered likely to be of vasovagal reflex etiology, comparing patients who had tilt-induced reflex response with those who did not. Tilt-induced reflex response was defined as spontaneous symptom reproduction with characteristic hypotension and bradycardia. Relationship of demographics and baseline supine BP to tilt-test were assessed using logistic regression models. Individual records of 5236 patients (45% males; mean age: 60 ± 22 years; 32% prescribed antihypertensive therapy) were analyzed. Tilt-positive (n = 3129, 60%) vs tilt-negative patients had lower SBP (127.2 ± 17.9 vs 129.7 ± 18.0 mmHg, p < 0.001), DBP (76.2 ± 11.5 vs 77.7 ± 11.7 mmHg, p < 0.001) and HR (68.0 ± 11.5 vs 70.5 ± 12.5 bpm, p < 0.001). In multivariable analyses, tilt-test positivity was independently associated with younger age (Odds ratio (OR) per 10 years:1.04; 95% confidence interval (CI), 1.01–1.07, p = 0.014), SBP ≤ 128 mmHg (OR:1.27; 95%CI, 1.11–1.44, p < 0.001), HR ≤ 69 bpm (OR:1.32; 95%CI, 1.17–1.50, p < 0.001), and absence of hypertension (OR:1.58; 95%CI, 1.38–1.81, p < 0.001). In conclusion, among patients with suspected reflex syncope, younger age, lower blood pressure and lower heart rate are associated with positive tilt-test result.
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| 4. |
- Johansson, Madeleine, et al.
(author)
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Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience
- 2021
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In: JACC Case Reports. - : Elsevier BV. - 2666-0849. ; 3:4, s. 573-580
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Journal article (peer-reviewed)abstract
- Major clinical centers in Sweden have witnessed an inflow of patients with chronic symptoms following initial outpatient care for coronavirus disease-2019 (COVID-19) infection, suggestive of postural orthostatic tachycardia syndrome. This report presents the first case series of 3 Swedish patients diagnosed with postural orthostatic tachycardia syndrome more than 3 months after the primary COVID-2019 infections.
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| 5. |
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| 6. |
- Kohno, Ritsuko, et al.
(author)
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Mast Cell Activation Disorder and Postural Orthostatic Tachycardia Syndrome : A Clinical Association
- 2021
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In: Journal of the American Heart Association. - 2047-9980. ; 10:17
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Journal article (peer-reviewed)abstract
- Background Recently there has been increased interest in a possible association between mast cell activation (MCA) disorder and postural orthostatic tachycardia syndrome (POTS). This study examined the frequency with which symptoms and laboratory findings suggesting MCA disorder occurred in patients diagnosed with POTS. Methods and Results Data were obtained from patients in whom symptoms and orthostatic testing were consistent with a POTS diagnosis. Individuals with <4 months symptom duration, evident ongoing inflammatory disease, suspected volume depletion, or declined consent were excluded. All patients had typical POTS symptoms; some, however, had additional nonorthostatic complaints not usually associated with POTS. The latter patients underwent additional testing for known MCA biochemical mediators including prostaglandins, histamine, methylhistamine, and plasma tryptase. The study comprised 69 patients who met POTS diagnostic criteria. In 44 patients (44/69, 64%) additional nonorthostatic symptoms included migraine, allergic complaints, skin rash, or gastrointestinal symptoms. Of these 44 patients, 29 (66%) exhibited at least 1 laboratory abnormality suggesting MCA disorder, and 11/29 patients had 2 or more such abnormalities. Elevated prostaglandins (n=16) or plasma histamine markers (n=23) were the most frequent findings. Thus, 42% (29/69) of patients initially diagnosed with POTS exhibited both additional symptoms and at least 1 elevated biochemical marker suggesting MCA disorder. Conclusions Laboratory findings suggesting MCA disorder were relatively common in patients diagnosed with POTS and who present with additional nonorthostatic gastrointestinal, cutaneous, and allergic symptoms. While solitary abnormal laboratory findings are not definitive, they favor MCA disorder being considered in such cases.
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| 7. |
- Nawaz, Sara, et al.
(author)
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Novel inflammatory biomarkers in postural orthostatic tachycardia syndrome
- 2023
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In: Europace. - 1532-2092 .- 1099-5129. ; , s. 345-345
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Conference paper (peer-reviewed)abstract
- IntroductionPostural Orthostatic Tachycardia Syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and orthostatic intolerance. While traditional inflammatory biomarkers tend to be normal, a subclinical inflammatory process may be present in POTS.PurposeWe aimed to analyse novel inflammatory biomarkers in POTS patients: Growth Differentiation Factor 15 (GDF15), Neutrophil Gelatinase Associated Lipocalin (NGAL), Intercellular Adhesion Molecule 1 (ICAM-1), Tumour Necrosis Factor Receptor 1 (TNFR1) and Tumour Necrosis Factor Receptor 2 (TNFR2) and compared them to healthy controls. These inflammatory biomarkers have been shown to be independent predictors of major adverse cardiovascular events in other populations.MethodsAn age- and sex-matched case-control study included 65 patients verified to have POTS by positive head-up tilt-testing and cardiovascular autonomic tests, and 65 healthy controls (mean age: 31.1 vs 31.5 years, 84% females) with negative active standing tests and no history of syncope, orthostatic intolerance, or endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure plasma levels of inflammatory biomarkers in a blinded fashion. Descriptive statistics compared groups and a univariate ANOVA was employed. Biomarker values were log-transformed. A score incorporating all biomarkers was generated to see if the totality of biomarkers discriminated POTS patients from controls.ResultsBaseline characteristics are displayed in Table 1. Mean levels of GDF15 (p=0.01), NGAL (p=0.003), ICAM-1 (p=0.04) and TNFR1 (p=0.03) were significantly higher in POTS vs controls, whereas TNFR2 (p=0.04) was significantly lower in POTS (p=0.04). The product of four upregulated biomarkers divided by TNFR2 produced a receiver operator curve (ROC) with an area under the curve (AUC) of 0.703 (pConclusionPOTS patients had increased GDF15, NGAL, TNFR1 and ICAM-1 levels and reduced TNFR2 levels suggesting underlying, yet undefined, subclinical inflammatory processes involving neutrophil and endothelial activation.
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| 8. |
- Olshansky, Brian, et al.
(author)
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Importance of resting heart rate
- 2023
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In: Trends in Cardiovascular Medicine. - : Elsevier BV. - 1873-2615 .- 1050-1738. ; 33:8, s. 502-515
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Research review (peer-reviewed)abstract
- Resting heart rate is a determinant of cardiac output and physiological homeostasis. Although a simple, but critical, parameter, this vital sign predicts adverse outcomes, including mortality, and development of diseases in otherwise normal and healthy individuals. Temporal changes in heart rate can have valuable predictive capabilities. Heart rate can reflect disease severity in patients with various medical conditions. While heart rate represents a compilation of physiological inputs, including sympathetic and parasympathetic tone, aside from the underlying intrinsic sinus rate, how resting heart rate affects outcomes is uncertain. Mechanisms relating resting heart rate to outcomes may be disease-dependent but why resting heart rate in otherwise healthy, normal individuals affects outcomes remains obscure. For specific conditions, physiologically appropriate heart rate reductions may improve outcomes. However, to date, in the normal population, evidence that interventions aimed at reducing heart rate improves outcomes remains undefined. Emerging data suggest that reduction in heart rate via vagal activation and/or sympathetic inhibition is propitious.
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| 9. |
- Ricci, Fabrizio, et al.
(author)
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Increased levels of circulating endostatin are linked to orthostatic hypotension
- 2023
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In: European Heart Journal. - 1522-9645 .- 0195-668X. ; 44:Supplement_2
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Conference paper (peer-reviewed)abstract
- BackgroundOrthostatic hypotension (OH) occurs when blood pressure regulation fails. The underlying molecular mechanism of OH remain largely unexplored. Endostatin is a biologically active molecule cleaved by matrix metalloproteinases, elastases and cathepsins from collagen XVIII in the extracellular matrix and inhibits angiogenesis. Circulating levels of endostatin have been proposed to be involved in blood pressure (BP) regulation, by inducing nitric oxide release. To date, the relationship between endostatin and OH have not been examined.PurposeWe aimed to investigate circulating levels of endostatin in patients with verified OH by tilt test at a tertiary syncope unit compared with healthy age- and sex-matched controls from the same geographical region.MethodsWe performed an age- and sex-matched case-control study in 150 patients with OH verified by positive head-up tilt-testing and other cardiovascular autonomic tests at a tertiary syncope unit, and 150 healthy controls with negative active standing tests and no history of syncope, orthostatic intolerance, and endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin in a blinded fashion. Receiver operating characteristic curves were constructed to analyze the discriminative ability of endostatin in OH compared with healthy controls. Multivariate logistic regression was used to assess the association between endostatin, OH and hemodynamic variables adjusting for age and sex.ResultsStudy characteristics are displayed in the Table. Patients with OH had significantly higher absolute levels of circulating endostatin compared with healthy controls (59,024 ± 2513 vs. 44,090 ± 1978 pg/mL, p<0.001). Multivariate-adjusted logistic regression analysis controlling for age, sex, minimum systolic and minimum diastolic BP during tilt, identified endostatin as an independent determinant for OH (beta-coefficient 0.80, p=0.025). The obtained area under the curve was 0.70, P<0.001, Figure).ConclusionsOur findings indicate that patients with orthostatic hypotension have increased circulating levels of endostatin, independent of age, sex, and hemodynamic variables. Our results highlight the relevance of investigating the molecular pathways related to orthostatic hypotension. Further studies are warranted to assess the prognostic and therapeutic role of endostatin assessment in individuals with orthostatic hypotension.
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| 10. |
- Ricci, Fabrizio, et al.
(author)
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Metoprolol disrupts inflammatory response of human cardiomyocytes via β-arrestin2 biased agonism and NF-κB signaling modulation
- 2023
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In: Biomedicine and Pharmacotherapy. - 0753-3322. ; 168
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Journal article (peer-reviewed)abstract
- Aims: Recent evidence supports non-class cardioprotective effects of metoprolol against neutrophil-mediated ischemia-reperfusion injury during exacerbated inflammation. Whether metoprolol exerts direct anti-inflammatory effect on cardiomyocytes is unknown. Accordingly, we aimed to investigate the direct anti-inflammatory effects of metoprolol in a cellular model of human induced pluripotent stem cell-derived cardiomyocytes (hiCMs) and to explore the role of β-arrestin2 (β-ARR2) biased agonism signaling pathway. Methods and results: hiCMs were treated with TNF-α for 24 h, followed by 4-hour treatment with metoprolol or esmolol. Electrical response of hiCMs to β1-selective blockade was assessed by microelectrode arrays technology. The effect on inflammatory and adhesion molecule expression was evaluated in wild-type and β-ARR2 silenced hiCMs. To silence β-ARR2 expression, hiCMs were transfected with a specific small interfering RNA targeting β-ARR2 mRNA and preventing its translation. TNF-α stimulation boosted the expression of IκB, NF-κB, IL1β, IL6, and VCAM1 in hiCMs. TNF-α-treated hiCMs showed similar physiological responses to metoprolol and esmolol, with no difference in field potential duration and beat period recorded. Adding metoprolol significantly decreased inflammatory response patterns in wild-type hiCMs by dampening TNF-α induced expression of NF-κB, IL1β, and IL6, but not in β-ARR2-knockout hiCMs. A similar response was not observed in presence of β1-selective blockade with esmolol. Conclusions: Metoprolol exerts a non-class direct anti-inflammatory effect on hi-CMs. β1-selective blockade with metoprolol disrupts inflammatory responses induced by TNF-α and induces significant inhibition of NF-κB signaling cascade via β-ARR2 biased agonism. If confirmed at clinical level, metoprolol could be tested and repurposed to treat cardiac inflammatory disorders.
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| 11. |
- Ricci, Fabrizio, et al.
(author)
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Orthostatic hypotension is associated with higher levels of circulating endostatin
- 2024
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In: European Heart Journal Open. - 2752-4191.
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Journal article (peer-reviewed)abstract
- AimsThe pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumor effects proposed to be involved in blood pressure (BP) regulation.MethodsWe compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH.ResultsEndostatin levels were significantly higher in OH patients (59,024 ± 2513 pg/mL) versus controls (44,090 ± 1978 pg/mL, p<0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing (p<0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95%CI 1.141-1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors.ConclusionCirculating endostatin is elevated in patients with orthostatic hypotension and may serve as a potential clinical marker of increased cardiovascular risk in patients with orthostatic hypotension. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms.
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| 12. |
- Statz, Giselle M., et al.
(author)
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Can Artificial Intelligence Enhance Syncope Management?: A JACC: Advances Multidisciplinary Collaborative Statement : State-of-the-Art Review
- 2023
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In: JACC: Advances. - 2772-963X. ; 2:3
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Research review (peer-reviewed)abstract
- Syncope, a form of transient loss of consciousness, remains a complex medical condition for which adverse cardiovascular outcomes, including death, are of major concern but rarely occur. Current risk stratification algorithms have not completely delineated which patients benefit from hospitalization and specific interventions. Patients are often admitted unnecessarily and at high cost. Artificial intelligence (AI) and machine learning may help define the transient loss of consciousness event, diagnose the cause, assess short- and long-term risks, predict recurrence, and determine need for hospitalization and therapeutic intervention; however, several challenges remain, including medicolegal and ethical concerns. This collaborative statement, from a multidisciplinary group of clinicians, investigators, and scientists, focuses on the potential role of AI in syncope management with a goal to inspire creation of AI-derived clinical decision support tools that may improve patient outcomes, streamline diagnostics, and reduce health-care costs.
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| 13. |
- Ståhlberg, Marcus, et al.
(author)
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Cardiovascular dysautonomia in postacute sequelae of SARS-CoV-2 infection
- 2023
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In: Journal of Cardiovascular Electrophysiology. - 1540-8167.
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Research review (peer-reviewed)abstract
- Coronavirus disease 2019 (COVID-19) has led to a worldwide pandemic that continues to transform but will not go away. Cardiovascular dysautonomia in postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection has led to persistent symptoms in a large number of patients. Here, we define the condition and its associated symptoms as well as potential mechanisms responsible. We provide a careful and complete overview of the topic addressing novel studies and a generalized approach to the management of individuals with this complex and potentially debilitating problem. We also discuss future research directions and the important knowledge gaps to be addressed in ongoing and planned studies.
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| 14. |
- Sutton, Richard, et al.
(author)
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Tilt testing remains a valuable asset
- 2021
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In: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X.
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Research review (peer-reviewed)abstract
- Head-up tilt test (TT) has been used for >50 years to study heart rate/blood pressure adaptation to positional changes, to model responses to haemorrhage, to assess orthostatic hypotension, and to evaluate haemodynamic and neuroendocrine responses in congestive heart failure, autonomic dysfunction, and hypertension. During these studies, some subjects experienced syncope due to vasovagal reflex. As a result, tilt testing was incorporated into clinical assessment of syncope when the origin was unknown. Subsequently, clinical experience supports the diagnostic value of TT. This is highlighted in evidence-based professional practice guidelines, which provide advice for TT methodology and interpretation, while concurrently identifying its limitations. Thus, TT remains a valuable clinical asset, one that has added importantly to the appreciation of pathophysiology of syncope/collapse and, thereby, has improved care of syncopal patients.
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| 15. |
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